Recreational abuse of newly emerging club drugs including atypical hallucinogens, which is exacerbated by internet websites, is a significant and growing national problem. Abuse of these drugs among adolescents and young adults is a particular concern. A series of studies in human volunteers will provide new information about the pharmacological mechanisms of action, comparative pharmacology, and abuse liability of three mechanistically different hallucinogen compounds that are of concern to national authorities and about which there are major gaps in our current understanding: salvinorin A (a ? opioid agonist), N,N-dimethyltryptamine (DMT, a 5-HT2A agonist), and dextromethorphan (an NMDA antagonist). For all three compounds, dose-effect studies using low to high doses in participants with histories of hallucinogen drug abuse will provide new information about subjective effects, psychiatric symptoms, behavioral/cognitive impairment, physiological effects, relative abuse liability, and possible persisting toxic consequences of use. Pharmacological mechanisms of action will be investigated by examining the effects of selective receptor antagonists and by systematically comparing pairs of drugs acting at different receptor sites. Specifically, the first three studies will focus on two short-acting, atypical hallucinogens: salvinorin A and DMT. The first study will use a double- blind, double-dummy design to compare the effects of inhaled vaporized salvinorin A and intravenous DMT across a wide range of doses and measures, characterizing both robust and subtle differences between the two compounds. The second and third studies will further explore mechanisms of action by examining interactions of both drugs with naltrexone (a selective opioid receptor antagonist) and ketanserin (a selective 5-HT2A antagonist). The subsequent three studies will focus on the relatively longer-acting compound dextromethorphan, which is a noncompetitive NMDA-antagonist found in over-the-counter cough and cold medications and abused at high doses as a hallucinogen. The fourth study will compare the dose-effects of oral dextromethorphan with oral psilocybin (a classic 5-HT2A-mediated hallucinogen with a duration of action similar to dextromethorphan) characterizing both robust and subtle differences between the two compounds. The fifth and sixth studies will further explore the mechanisms of action of dextromethorphan (vs. psilocybin) by examining interactions with naltrexone (opioid antagonists are used clinically to treat dextromethorphan overdose) and ketanserin. Overall, this research program exploring the comparative pharmacology and specific mechanisms of action of salvinorin A, DMT, and dextromethorphan will have relevance to the development of prevention and treatment strategies for the abuse of these emerging abused hallucinogen drugs. Regarding public health more generally, this research has potentially wide-ranging implications for understanding the neurobiological basis of psychiatric and neurological disorders that involve the ? opioid, 5- HT, and NMDA receptor pathways.